The fascinating phenotypic spectrum of SCN1A gain-of-function epilepsies.

Abstract

SCN1A, long referred to as the most important epilepsy gene, continues to deliver exciting scientific surprises. It has always been associated with a broad phenotypic spectrum ranging from developmental and epileptic encephalopathies (DEEs), with Dravet syndrome being the prototypic and most frequent form, to self-limited, pharmacoresponsive phenotypes within the GEFS+ (Genetic Epilepsy with Febrile Seizures Plus) spectrum.1, 2 These disorders are due to loss-of-function (LoF) pathogenic variants. In 2017, we described the far more profound Early Infantile DEE (EIDEE) due to SCN1A pathogenic missense variants, associated with a hyperkinetic movement disorder.3 Onset was in the first 3 months of life and included seizure types not seen in Dravet syndrome, such as epileptic spasms. Our original seven patients included six with the recurrent missense pathogenic variant, T226M. We postulated that SCN1A-EIDEE was due to gain of function (GoF) of the sodium channel, given its phenotypic similarity to SCN2A-EIDEE and SCN8A-EIDEE, a hypothesis later proven with elegant dynamic action patch clamping studies.4 Increasing recognition of the spectrum of SCN1A GoF disorders, and epilepsies in particular, has occurred in the past few months. Brunklaus and colleagues extended the GoF phenotypic spectrum to include neonatal onset DEE, falling within the onset period of EIDEE.5 The International League Against Epilepsy definition for infants with onset of a DEE under 3 months is now "early infantile" rather than "early onset," as the latter term is often used imprecisely to encompass many ages of onset.6 The extended spectrum of SCN1A GoF epilepsies included babies with arthrogryposis, including some who died in utero with arthrogryposis on antenatal studies.5 In this issue, two studies add to the emerging spectrum of SCN1A GoF epilepsies, with functional studies deepening our understanding of the physiological consequences and highlighting critical therapeutic implications. Marticardi and coauthors describe the widening GoF spectrum, confirming the EIDEE phenotypes and bringing novel insights to the milder end of the SCN1A GoF epilepsies.7 They report patients with focal epilepsies beginning in infancy or childhood, at a median of 7.5 years, in the setting of normal intellect or mild impairment. These focal epilepsies are often inherited, and febrile seizures are not prominent. The recurrent SCN1A p.R1636Q pathogenic variant has now been identified in 12 individuals, including four reported by Clatot and coauthors.8 They show mixed gain and loss of function changes on physiological studies, resulting in an overall moderate GoF. Identical variants in paralogous sodium channel subunit genes show similar functional effects, underlining the supportive information that can be gleaned from functional studies in related genes. There remains a significant disparity between the severity in GoF and phenotypic outcome. Matricardi et al. demonstrate a more severe GoF across a range of biophysical parameters in the SCN1A variants causing EIDEE compared with those associated with infantile and childhood focal epilepsies.7 However, the epilepsies present a moderate GoF compared with the marked GoF seen with SCN1A pathogenic variants associated with hemiplegic migraine.9 Why this discordance between the degree of GoF and phenotype? There is no doubt that the variant is key, likely influenced by the cell type, genetic background, and early life effects that the GoF has on synaptic remodeling and plasticity. Distinction of SCN1A GoF EIDEE from Dravet syndrome early in life is essential and requires an understanding of the phenotypic differences. Seizure onset in SCN1A-EIDEE is usually by 3 months of age,3, 5 whereas the mean onset age in Dravet syndrome is 6 months. As rare patients with Dravet syndrome have onset between 6 weeks and 3 months,10 the overlap in age at onset can make it challenging to distinguish at onset, yet each diagnosis carries quite different treatment implications. Key differences include the presence of tonic seizures in EIDEE, with epileptic spasms in some, as well as a hyperkinetic movement disorder in many, and severe developmental delay. Many clinicians equate the finding of a pathogenic variant in SCN1A with Dravet syndrome, but these studies emphasize the need for a deeper understanding of SCN1A epilepsies. Hence, education regarding the full spectrum of LoF and GoF phenotypes is critical to ensure patients receive therapies appropriately targeting their genetic defect. So what does this mean for clinical practice? Physicians need an acute awareness of establishing whether an SCN1A pathogenic variant results in loss or gain of sodium channel function. Such information may not be readily available unless it is a recurrent variant with published functional studies. If not, nearby pathogenic variants with functional data may provide useful insights, as may similar variants in paralagous genes. This issue has treatment implications, with Matricardi et al. emphasizing the efficacy of sodium channelblocking antiseizure medications such as carbamazepine, phenytoin, lamotrigine, and oxcarbazepine, in their GoF cohort, independent of phenotype.7 This stands in stark contrast to the widespread teaching that sodium channel blockers (SCBs) exacerbate seizures in LoF SCN1A epilepsies such as Dravet syndrome.11 Although this is true of carbamazepine and oxcarbazepine, not all SCBs are necessarily contraindicated, as lamotrigine and phenytoin have been beneficial in some patients.12, 13 Clatot and colleagues point out that consideration of the nature of the functional dysregulation may be taken to a more nuanced level.8 In GoF patients, oxcarbazepine, which stabilizes the fast-inactivated state of the sodium channel, has been championed. As the major finding of their functional studies was increased persistent current, lacosamide, which acts on the slow-inactivated state, may be a more appropriate targeted therapy for GoF epilepsies. These observations highlight the need for far greater insights into the physiological impact of specific pathogenic variants and their implications for early, efficacious treatment to optimize outcomes for individuals with SCN1A epilepsies. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. I.E.S. has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, Garvan Institute of Medical Research 2023, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from BioMarin, Biocodex, Chiesi, Eisai, GlaxoSmithKline, LivaNova, Nutricia, UCB, and Zuellig Pharma; has received funding for travel from Biocodex, BioMarin, Eisai, Encoded Therapeutics, GlaxoSmithKline, and UCB; has served as an investigator for Anavex Life Sciences, Cerecin, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; has consulted for Atheneum Partners, Biohaven Pharmaceuticals, BioMarin, Care Beyond Diagnosis, Encoded Therapeutics, Epilepsy Consortium, Ovid Therapeutics, UCB, and Zynerba Pharmaceuticals; and is a nonexecutive director of Bellberry and a director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies. She may accrue future revenue on pending patent WO61/010176 (filed 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; and has a patent Molecular Diagnostic/Theranostic Target for Benign Familial Infantile Epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID: 2012-009).